Transdermal absorption is currently one of the fastest growing methods of drug delivery. Transdermal therapeutic systems are self-contained dosage forms that, when applied to intact skin, deliver drug(s) at a controlled rate to the systemic circulation. Advantages of using the transdermal route include: enhanced therapeutic efficacy, reduction in the frequency of dosing, reduction of side effects due to optimization of the blood-concentration versus time profile, increased patient compliance due to elimination of multiple dosing schedules, bypassing the hepatic "first-pass" metabolism , avoiding gastrointestinal incompatibilities and providing a predictable and extended duration of activity. However, the main function of the skin is to act as a barrier to entering compounds. As a consequence, transdermal therapy has so far been restricted to a limited number of drugs that possess the desirable physiochemical properties for diffusion across the skin barrier. One effective method of overcoming the barrier function of the skin is to include a penetration enhancer in the formulation of a transdermal therapeutic system. See Barry, Brian W.: Dermatological Formulations: Percutaneous Absorption (Dekker, New York, 1983); Bronough et al, Percutaneous Absorption, Mechanisms-Methodology-Drug Delivery, (Marcel Dekker, New York, NY 1985); and Monkhouse et al, Transdermal drug delivery-problems and promises. Drug Dev. Ind. Pharm., 14, 183-209 (1988).
A penetration enhancer is a chemical compound that, when included in a formulation, temporarily increases the permeability of the skin to the drug allowing more of the drug to be absorbed in a shorter period of time. Several different types of penetration enhancers have been reported such as dimethylsulfoxide, n-decyl methyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, 1-dodecylazacycloheptan-2-one (Azone), propylene glycol, ethanol, pyrrolidones such as N-methyl-2-pyrrolidone (NMP) and surfactants. See Bronough et al, supra, and Stoughton et al, Azone: A New Non-toxic enhancer of percutaneous penetration. Drug Dev. Ind. Pharm., 9, 725-744 (1983).
N-methyl-2-pyrrolidone is a versatile solvent which is miscible with water, ethyl alcohol, ether, chloroform, benzene, ethyl acetate and carbon disulfide. N-methylpyrrolidone has been widely used as a solvent in industrial processes such as petroleum refining, GAF Corp.: "M-Pyrol (N-methyl-2-pyrrolidone) Handbook.", GAF Corp., New York, 1972. It is currently used as a solubilizing agent in topical and parenteral veterinary pharmaceuticals and is now under consideration for use in products intended for humans, Wells, D. A. et al: Disposition and Metabolism of Double-Labeled [.sup.3 H and .sup.14 C] N-methyl-2-pyrrolidone in the Rat. Drug Met. Disps., 16, 243-249 (1988). Animal and human experiments have shown very little irritation or sensitization potential. Ames type assays and chronic exposure studies have not revealed any significant toxicity, Wells et al, Mutagenicity and Cytotoxicity of N-methyl-2-pyrrolidone and 4-(methyl amino) Butanoic Acid in the Salmonella/microsome Assay. J. Appl. Tox., 8, 135-139 (1988). N-methylpyrrolidone has also been shown to be an effective penetration enhancer. Barry et al, Optimization of Bioavailability of Topical Steroids Penetration Enhancers Under Occlusion. J. Inv. Derm., 82, 49-52 (1984); Akter et al, Absorption Through Human Skin of Ibuprofen and Flurbiprofen; Effect of Dose Variation, Deposited Drug Films, Occlusion and the Penetration Enhancer N-methyl-2-pyrrolidone. J. Pharm. Pharmacol., 37, 27-37 (1984); Holegaard et al, Vehicle Effect on Topical Drug Delivery IV. Effect of N-methylpyrrolidone and Polar Lipids on Percutaneous Transport. Int. J. Pharm., 43, 233-240 (1988); Sugibayashi et al, Effect of Several Penetration Enhancers on the Percutaneous Absorption of Indomethacin in Hairless Rat. Chem. Pharm. Bull., 36, 1519-1528 (1988); Bennett et al, Optimization of Bioavailability of Topical Steroids: Non-Occluded penetration Enhancers Under Thermodynamic Control. J. Pharm. Pharmacol., 37, 298-304 (1985); Sasaki et al, Enhancing Effect of Pyrrolidone Derivatives on Transdermal Drug Delivery. 1. Int. J. Pharm., 44, 15-24 (1988); Lee et al, Toxicity of N-methyl-2-pyrrolidone (NMP): Tetratogenic, Subchronic and Two-Year Inhalation Studies, Fund. Appl. Tox., 9, 222-235 (1987).
There remains a need in the art of transdermal delivery for a penetration enhancer which is safe, effective, and provides advantages not known to penetration enhancers of the prior art.